Verbundene Projekte

MicroRNAs role in brown and white adipose tissue differentiation and function

01.08.2013

SNF-Förderungsprofessuren

Abstract

Brown adipose tissue catabolizes lipids and sugars to produce heat. Brown fat cells also emerge in the subcutaneous white fat (known as “beige” cells) a process referred to as browning. Increased beige fat development promotes energy expenditure, improves insulin sensitivity and is associated with a lean and healthy phenotype. Browning appears consequent to physiological stimuli such as cold exposure or endurance exercise, and interventional stimuli such as microbiota depletion and Roux-en-Y Gastric Bypass Weight-Loss Surgery. It remains unknown what could be the common feature and possible common mechanism between the physiological and interventional conditions that promote browning, and what is the origin of the newly developed beige cells during these various stimuli. A characteristic of all these browning stimuli is the negative energy balance: the energy uptake is lower than the energy expenditure resulting in weight loss primarily due to the decreased fat mass.Caloric restriction (CR) is a classical example of energy scarcity. CR up to 40% of nutritious diet intake without malnutrition extends healthy lifespan from yeast to mammals, delays the onset of multiple age-associated diseases and improves metabolic health. The intestinal microbiota co-develops with the host and influences the whole-body metabolism by affecting energy balance. According to our recent data, CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size. We also showed that cold-induced shift of the microbiota composition alone is sufficient to induce tolerance to cold, improved insulin sensitivity, increased energy expenditure as well as lower fat content, and this effect is at least in part mediated by browning of the white fat depots.With the proposed research we aim at identifying and characterizing the upstream mechanisms leading to browning following CR. The microbiota transplantation experiments would demonstrate whether the browning induced upon CR is mediated by the changes in the gut bacterial populations. We will uncover bacterial strains that are likely to play a role in the beige fat development. Thus characterizing them, and investigating their importance would suggest further means of promoting the beige fat development. Moreover, we will uncover the origin of the beige fat during caloric restriction and microbiota depletion, and we will provide new insights to the beige fat development during these browning stimuli. Finally, we believe that this project would provide at least one direct mechanistic link between the microbiota changes and the beige fat development and would also be an important resource for future studies on the metagenomic changes induced by caloric restriction and cold exposure. Together, we expect to establish and characterize a novel axis that leads to beige fat development, and provide mechanistic and metagenomic explanation for its appearance. We believe that manipulating the gut microbiota and exploiting the mechanistic link to the beige fat induction revealed by the proposed study would be of conceptual importance for our understanding of the beige fat development that could lead to development of novel therapeutic approaches for improving insulin sensitivity and reducing the obesity-induced diabetes onset.